The major hypothesis of this project is that the control of leishmaniasis in individuals with sub-clinical L.braziliensis infection is performed by innate immune response and that skin associated cytokines and CD8+ T cells participate of tissue damage leading development of cutaneous leishmaniasis (CL), mucosal leishmaniasis and disseminated leishmaniasis (DL). The major aims are: Aimi) To determine how innate cells control L. braziliensis parasites. Our finding that a large number of individuals (subclinical) who are infected by L.braziliensis will control the parasites without developing disease provides a unique opportunity to define how natural resistance may be occurring to L.braziliensis. We propose to: a) define the mechanism(s) involved in the killing of parasites by neutrophils and macrophages; b) determine if neutrophils and macrophages from patients with different forms ofthe disease exhibit differences in their capacity to kill parasites; Aim2) To determine what skin-associated cytokines contribute to the pathologic responses following L. braziliensis infecfion. We found that thymic stromal lymphopoietin (TSLP), a cytokine produced by epithelial cells at barrier surfaces, is highly expressed in the epidermis of lesions from CL pafients. We propose to: a) determine the effect of TSLP in macrophage and dendritic cells (DCs) infected with L. braziliensis; b) determine the role of TSLP in CD4+ T and CD8+ T cell proliferation and funcfion; and c) correlate the expression of TSLP in lesions from different clinical phenotypes with T cell function. Aim3) To determine how CD8 T cells participate in the immunopathology in patients infected with L. braziliensis. Since our preliminary data indicate that CD8 T cells exhibit increased levels of granzyme as the lesions worsen, we hypothesize that CD8 T cells contribute to the pathology seen in patients, and propose to: a) determine the mechanisms involved in the recruitment of CD8+ T cells to cutaneous lesion sites; b) determine the frequency and the balance of inflammatory versus regulatory CD8+ T cell subpopulations in the blood and lesions from CL patients; and c) compare the ability of CD8+ T cells from SC individuals and CL patients to promote killing of L. braziliensis infected macrophages in vitro.